Blood-sugar levels in humans are controlled by insulin, glucagon, adrenalin, growth hormone, etc. The hyperglycemic state caused by the abnormality of this controlling mechanism is called diabetes mellitus. Diabetes mellitus is categorized into type I diabetes (insulin-dependent diabetes mellitus, or IDDM) and type II diabetes (non-insulin-dependent diabetes mellitus, or NIDDM). Type I diabetes is caused by the absolute decrease of insulin secretion, and type II diabetes is caused by the relative decrease of insulin secretion or the diminished insulin sensitivity of peripheral tissues and the liver. Type II diabetes that is not accompanied by obesity is considered to be typically caused by the decrease of insulin secretion, and type II diabetes that is accompanied by obesity is considered to be typically caused by diminished insulin sensitivity. Moreover, in addition to insulin, glucagon is also considered to be involved in the cause of diabetes mellitus.
Glucagon is a peptide hormone composed of 29 amino acids secreted from the pancreatic islet α-cells. Glucagon raises blood sugar levels by promoting glycogenolysis and glucogenesis. Glucagon is bound to a seven-transmembrane, G protein-coupled receptor present at the cell membrane, and expresses its physiological functions via cAMP as the second messenger.
In type II diabetic patients, blood glucagon levels are increased, and hepatic glucose production is enhanced accordingly, resulting in a high blood sugar condition. This suggests that controlling the function of glucagon could be used to control hepatic glucose production, decreasing blood sugar levels, and ameliorating the high blood sugar conditions of diabetic patients.
It has been reported that peptidergic glucagon receptor antagonists decrease blood sugar levels of diabetic animal models (Science 1982, 215, 1115-1116; Peptides 1989, 10, 1171-1177; Diabetes 1996, 45(Suppl2), 220A). However, it is a problem that the peptidergic glucagon receptor antagonists are susceptible to enzymolysis and do not have activities from oral administration.
Although several nonpeptidergic glucagon receptor antagonists have been proposed, none are used clinically yet. Therefore, it has been strongly desired to develop an excellent nonpeptidergic glucagon.
WO 99/01423 discloses that a hydrazide compound represented by Formula (1) below functions as a glucagon antagonist or an inverse agonist:
wherein R1 and R2 are independently hydrogen or lower alkyl, or together form a valence bond;    R3 and R4 independently are hydrogen or lower alkyl;    n is 0, 1, 2 or 3;    m is 0 or 1;    X is >C═O, >C═S, >═NR5 or >SO2;    A is a group represented by one of the following groups:
(wherein R7 is hydrogen, halogen, —CN, —CF3, —OCF3, —OCH2CF3, —NO2, —OR11, —NR11R12, lower alkyl, aryl, aryl-lower alkyl, —SCF3, —SO2NR11R12, —SR11, —CHF2, —OCHF2, —OSO2R11, —CONR11R12, —OCH2CONR11R12, —CH2OR11, —CH2NR11R12, —OCOR11, —CO2R13 or —OSO2CF3;    R8 and R9 independently are hydrogen, halogen, —CN, —CF3, —OCF3, —OCH2CF3, —NO2, —OR11, —NR11R12, lower alkyl, aryl, —SCF3, —SR11, —CHF2, —OCHF2, —OSO2R11, —CONR11R12, —CH2OR11, —CH2NR11R12, —OCOR11, —CO2R13 or —OSO2CF3, or R8 and R9 together form —OCH2O— or —OCH2CH2O—;    R11 and R12 independently are hydrogen, —COR13, —SO2R13, lower alkyl or aryl;    R13 is hydrogen, lower alkyl, aryl-lower alkyl or aryl; and    R10 is hydrogen, lower alkyl, aryl-lower alkyl or aryl);    B is a group represented by the following formula:
(wherein R14 and R15 independently are hydrogen, halogen, —CN, —CF3, —OCF3, —O(CH2)1CF3, —NO2, —OR16, —NR16R17, lower alkyl, aryl, aryl-lower alkyl, —SCF3, —SR16, —CHF2, —OCHF2, —OCF2CHF2, —OSO2CF3, —CONR16R17, —(CH2)1CONR16R17, —O(CH2)1CONR16R17, —(CH2)1COR16, —(CH2)1 OR16, —O(CH2)1OR16, —(CH2)1NR16R17, —O(CH2)1NR16R17, —OCOR16, —CO2R18, —O (CH2)1CO2R18, —O(CH2)1CN or —O(CH2)1Cl, or R14 and R15 together form —O(CH2)1O— or —(CH2)1—;    1, 2, 3 or 4;    R16 and R17 independently are hydrogen, —COR18, —SO2R18, lower alkyl or aryl, or R16 and R17 together form a C2-7 cyclic alkyl bridge;    R18 is hydrogen, lower alkyl, aryl or aryl-lower alkyl;    W is —N═ or —CR19═;    Y is —N═ or —CR20═;    Z is —N═ or —CR21═;    V is —N═ or —CR22═; and    Q is —N23, —O— or —S—);    K is a group represented by the following formula:
    D is hydrogen or a group represented by the following formula:
(wherein Y′ is —N═ or —CR32═;    Z′ is —N═ or —CR33═;    V′ is —N═ or —CR34═;    W′ is —N═ or —CR35═;    R27, R28, R32, R33, R34 and R35 independently are hydrogen, halogen, —CN, —CF3, —O(CH2)yCF3, —(CH2)yNHCOCF3, —NO2, lower alkyl, aryl, aryl-lower alkyl, —SCF3, —SR29, —CHF2, —OCHF2, —OCF2CHF2, —OSO2R29, —OSO2CF3, —(CH2)yCONR29R30, —O(CH2)yCONR29R30, (CH2)yOR29, (CH2)yNR29R30, —OCOR29, —COR29 or —CO2R29, or    R27 and R28, R32 and R33, R33 and R34, or R34 and R35 together form —O(CH2)yO—; and    y is 0, 1, 2, 3 or 4).
Although the claims of the aforementioned PCT application include a great number of compounds, it discloses the compound represented by Formula (2) below as the only specific example of a compound represented by the aforementioned Formula (1) wherein B is a furan ring.

WO 00/39088 discloses compounds having chemical structures similar to those of the compounds disclosed in WO99/01423 and also teaches that they can be used as a glucagon antagonist or an inverse agonist.
Japanese Unexamined Patent Publication No. 91061/1973 (Chem. Abstr. 1974, 80, 120745v) discloses that a diphenyl furan derivative represented by Formula (3) below has antibacterial and antiprotozoal actions, and is useful as a pharmaceutical or animal drug:
wherein R1 and R1′ are the same or different, and independently represent a hydrogen atom, a lower alkyl or lower alkoxy group; R2 is a hydrogen atom or a nitro group; and R3′ is an acyl group or an arylsulfonyl group.
However, the aforedmentioned patent publication discloses only the following 9 compounds shown in Table 1 as 2-furancarboxylic acid 2-acylhydrazide compounds:
TABLE 1 R2R3′H2-furoylH5-methyl-2-furoylNO2AcetylNO25-methyl-2-furoylNO25-bromo-2-furoylNO2isonicotinoylNO24-chlorobenzoylNO23,4-diphenyl-2-furoylNO25-nitro-3,4-diphenyl-2-furoyl